Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor

ABSTRACT

A method is provided for inhibiting onset of or treating migraine headache by administering an ACE inhibitor, such as captopril, alone or in combination with a calcium channel blocker such as diltiazem or nifedipine, over a prolonged period of treatment.

REFERENCE TO OTHER APPLICATIONS

This is a continuation-in-part of application Ser. No. 118,131, filedNov. 9, 1987 now abandoned.

FIELD OF THE INVENTION

The present invention relates to a method for inhibiting onset of ortreating migraine headaches by administering an ACE inhibitor, such ascaptopril, zofenopril, fosinopril or enalapril, alone or in combinationwith a calcium channel blocker, such as diltiazem or nifedipine.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 4,046,889 and 4,105,776 to Ondetti et al disclosesproline derivatives which are angiotensin converting enzyme (ACE)inhibitors and have the general formula ##STR1## wherein

R is hydroxy, NH₂ or lower alkoxy;

R₁ and R₄ each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;

R₂ is hydrogen, lower alkyl, phenyl, substituted phenyl wherein thephenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-loweralkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, loweralkylthiomethyl, phenyl-lower alkylthiomethyl, loweralkanoyl-amidomethyl, ##STR2##

R₃ is hydrogen, hydroxy or lower alkyl;

R₅ is lower alkyl, phenyl or phenyl-lower alkyl;

R₆ is lower alkyl, phenyl, substituted phenyl (wherein the phenylsubstituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkylor amino(carboxy)lower alkyl;

R₇ is ##STR3##

M is O or S; m is 1 to 3; n and p each is 0 to 2.

The asterisks indicate asymmetric carbon atoms. Each of the carbonsbearing a substituent R₁, R₃ and R₄ is asymmetric when that substituentis other than hydrogen.

These patents disclose captopril.

U.S. Pat. No, 4,168,267 to Petrillo discloses phosphinylalkanoylprolines which have the formula ##STR4## wherein

R₁ is lower alkyl, phenyl or phenyl-lower alkyl;

R₂ is hydrogen, phenyl-lower alkyl or a metal ion;

R₃ is hydrogen or lower alkyl;

R₄ is hydrogen, lower alkyl, phenyl-lower alkyl or a metal ion; and

n is 0 or 1.

U.S. Pat. No. 4,337,201 to Petrillo discloses phosphinylalkanoylsubstituted prolines having the formula ##STR5## or a salt thereof,wherein R₁ is alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;one of R₂ and R₄ is ##STR6## and the other is hydrogen, alkyl aryalkylor ##STR7## wherein X is hydrogen, alkyl or phenyl and Y is hydrogen,alkyl, phenyl or alkoxy, or together X and Y are --(CH₂)₂ --, --(CH₂)₃--, --CH═CH--or ##STR8##

R₃ is hydrogen or alkyl;

--R₅ --COOR₄ is ##STR9##

R₆ is hydrogen, hydroxy, alkyl, halogen, azido, amino, cycloalkyl, aryl,arylalkyl, carbamoyloxy, N,N-dialkylcarbamoyloxy, or --Z--R9;

R₇ and R'₇ are the same and each is halogen or --Z--R₁₀, or R₇ and R'₇together are ═O, --O--(CH₂)_(m) --O--or --S--(CH₂)_(m) --S--;

R₈ is hydrogen and R'₈ is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl orR₈ and R'₈ together are═O;

R₉ is alkyl, aryl, arylalkyl, 1-- or 2-naphthyl, or biphenyl;

R₁₀ is alkyl, aryl or arylalkyl;

Z is oxygen or sulfur;

n is 0 or 1; and

m is 1 or 2.

The Petrillo patent covers fosinopril ##STR10##

U.S. Pat. No. 4,432,971 to Karanewsky et al discloses phosphonamidatesubstituted amino or imino acids which are angiotensin converting enzymeinhibitors and salts thereof and have the formula ##STR11## wherein X isan imino or amino acid of the formula ##STR12##

R₇ is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR13## azido,amino, ##STR14## a 1- or 2-naphthyl of the formula ##STR15## --(CH₂)_(m)-cycloalkyl, ##STR16## --O-lower alkyl, ##STR17## a 1- or 2-naphthyloxyof the formula ##STR18## --S-lower alkyl, ##STR19## or a 1- or2-naphthylthio of the formula ##STR20##

R₈ is keto, halogen, ##STR21## --O-lower alkyl, a 1- or 2-naphthyloxy ofthe formula ##STR22## --S-lower alkyl, ##STR23## or a 1- or2-naphthylthio of the formula ##STR24##

R₉ is keto or ##STR25##

R₁₀ is halogen or --Y--R₁₆,

R₁₁, R'₁₁, R₁₂ and R'₁₂ are independently selected from hydrogen andlower alkyl or R'₁₁, R₁₂ and R'₁₂ are hydrogen and R₁₁ is ##STR26##

R₁₃ is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro,trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.

R₁₄ is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro,trifluoromethyl or hydroxy.

m is zero, one, two or three.

p is one, two or three provided that p is more than one only if R₁₃ orR₁₄ is hydrogen, methyl, methoxy, chloro or fluoro.

R₁₅ is hydrogen or lower alkyl of 1 to 4 carbons.

Y is oxygen or sulfur.

R₁₆ is lower alkyl of 1 to 4 carbons, ##STR27## or the R₁₆ groups jointo complete an unsubstituted 5- or 6-membered ring or said ring in whichone or more of the carbons has a lower alkyl of 1 to 4 carbons or adi(lower alkyl of 1 to 4 carbons) substituent.

R₄ is hydrogen, lower alkyl, cycloalkyl, or ##STR28##

R₅ is hydrogen, lower alkyl, ##STR29##

r is an integer from 1 to 4,

R₁ is hydrogen, lower alkyl or cycloalkyl.

R₂ is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR30##

or R₁ and R₂ taken together are --(CH₂)_(n) -- wherein n is an integerfrom 2 or 4.

R₃ and R₆ are independently selected from hydrogen, lower alkyl, benzyl,benzhydryl, or ##STR31## wherein R₁₇ is hydrogen, lower alkyl, orphenyl, and R₁₈ is hydrogen, lower alkyl, lower alkoxy, phenyl, or R₁₇and R₁₈ taken together are --(CH₂)₂ --, --(CH₂)₃ --, --CH═CH--, or##STR32##

R₁₉ is lower alkyl, benzyl, or phenethyl.

R₂₀ is hydrogen, lower alkyl, benzyl or phenethyl.

R₂₁ is alkyl of 1 to 10 carbons, ##STR33## wherein q is zero or aninteger from 1 to 7 and R₁₄, p and m are as defined above.

R₂₂ and R₂₃ are independently selected from hydrogen, lower alkyl, halosubstituted lower alkyl, ##STR34## wherein m, R₁₄, and p are as definedabove.

U.S. Pat. No. 4,374,829 discloses carboxyalkyl dipeptide derivativeswhich are said to be angiotensin converting enzyme inhibitors and havethe formula ##STR35## wherein R and R⁶ are the same or different and arehydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy(dimethylaminoethoxy), acylamino lower alkoxy (acetylamino-ethoxy),acyloxy lower alkoxy (pivaloyloxymethoxy), aryloxy, such as phenoxy,arylloweralkoxy, such as benzyloxy, substituted aryloxy or substitutedarylloweralkoxy wherein the substituent is methyl, halo, methoxy, amino,loweralkylamino, diloweralkylamino, hydroxyamino, arylloweralkylaminosuch as benzylamino;

R¹ is hydrogen, alkyl of from 1 to 20 carbon atoms which includebranched and cyclic and unsaturated (such as allyl) alkyl groups,substituted loweralkyl wherein the substituent can be halo, hydroxy,lower alkoxy, aryloxy such as phenoxy, amino, diloweralkylamino,acylamino, such as acetamido and benzamido, arylamino, guanidino,imidazolyl, indolyl, mercapto, loweralkylthio, arylthio such asphenylthio, carboxy or carboxamido, carboloweralkoxy, aryl such asphenyl or naphthyl, substituted aryl such as phenyl wherein thesubstituent is lower alkyl, lower alkoxy or halo, arylloweralkyl,arylloweralkenyl, heteroaryllower alkyl or heteroaryllower alkenyl suchas benzyl, styryl or indolyl ethyl, substituted arylloweralkyl,substituted arylloweralkenyl, substituted heteroaryllower alkyl, orsubstituted heteroaryllower alkenyl, wherein the substituents(s) ishalo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl,acylamino (acetylamino or benzoylamino) diloweralkylamino,loweralkylamino, carboxyl, haloloweralkyl, cyano or sulfonamido;arylloweralkyl or heteroarylloweralkyl substituted on the alkyl portionby amino or acylamino (acetylamino or benzoylamino);

R² and R⁷ are the same or different and are hydrogen or lower alkyl;

R³ is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyllower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acylaminolower alkyl (such as benzoylamino lower alkyl, acetylamino lower alkyl),amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl,guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl,mercapto lower alkyl, lower alkylthio lower alkyl;

R⁴ is hydrogen or lower alkyl;

R⁵ is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyllower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino loweralkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkylor lower alkylthio lower alkyl;

R⁴ and R⁵ may be connected together to form an alkylene bridge of from 2to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms andone sulfur atom, an alkylene bridge of from 3 to 4 carbon atomscontaining a double bond or an alkylene bridge as above substituted withhydroxy, loweralkoxy, lower alkyl or dilower alkyl;

and the pharmaceutically acceptable salts thereof.

Example 41 of U.S. Pat. No. 4,374,829 describes the preparation ofN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

U.S. Pat. No. 4,452,790 to Karanewsky et al is directed to phosphonatesubstituted amino or imino acids and salts thereof having the formula##STR36## wherein X is an imino or amino acid of the formula ##STR37##

R₄ is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR38## azido,amino, ##STR39## a 1- or 2-naphthyl of the formula ##STR40## a 1- or2-naphthyloxy of the formula ##STR41## or a 1- or 2-naphthylthio of theformula ##STR42##

R₅ is keto, halogen, ##STR43## --O-lower alkyl, a 1- or 2-naphthyloxy ofthe formula ##STR44## --S-lower alkyl, ##STR45## or a 1- or2-naphthylthio of the formula ##STR46##

R₇ is keto or ##STR47##

Each R₈ is independently halogen or --Y--R₁₄.

R₉, R₉ ', R₁₂ and R₁₀ ' are independently selected from hydrogen andlower alkyl or R₉ ', R₁₀ and R₁₀ ', are hydrogen and R₉ is ##STR48##

R₁₁ is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro,trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.

R₁₂ is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro,trifluoromethyl or hydroxy.

m is zero, one, two or three.

p is one, two or three provided that p is more than one only if R₁₁ orR₁₂ is hydrogen, methyl, methoxy, chloro or fluoro.

R₁₃ is hydrogen or lower alkyl of 1 to 4 carbons.

Y is oxygen or sulfur.

R₁₄ is lower alkyl of 1 to 4 carbons, ##STR49## or the R₁₄ groups jointo complete an unsubstituted 5- or 6-membered ring or said ring in whichone or more of the carbons has a lower alkyl of 1 to 4 carbons or adi(lower alkyl of 1 to 4 carbons) substituent.

R₂₁ is hydrogen, lower alkyl, cycloalkyl, phenyl or ##STR50##

R₂₂ is hydrogen, lower alkyl, ##STR51##

r is an integer from 1 to 4.

R₁ is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR52## whereinq is zero or an integer from 1 to 7 and R₁₂ and p are as defined above.

R₁₉ and R₂₀ are independently selected from hydrogen, lower alkyl, halosubstituted lower alkyl, ##STR53## wherein m, R₁₁, and p are as definedabove.

R₂ is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR54##wherein r is as defined above.

R₃ and R₆ are independently selected from hydrogen, lower alkyl, benzyl,alkali metal such as Li, Na or K, benzhydryl, or ##STR55## wherein R₁₅is hydrogen, lower alkyl, cycloalkyl or phenyl, and R₁₆ is hydrogen,lower alkyl, lower alkoxy, phenyl, or R₁₅ and R₁₆ taken together are--(CH₂)₂ --, --(CH₂)₃ --, --CH═CH--, or ##STR56##

R₁₇ is lower alkyl, benzyl, or phenethyl.

R₁₈ is hydrogen, lower alkyl, benzyl or phenethyl.

This patent covers(S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline(SQ 29, 852).

U.S. Pat. No. 4, 248,883 to Sawayame et al discloses1-(3-mercapto-2-methylpropanoyl)-prolyl amino acid derivatives of theformula ##STR57## wherein R represents a hydrogen atom, a lower alkylgroup, a phenyl-lower alkyl group or a substituted phenyl-lower alkylgroup; R₁ represents a hydrogen atom, R₄ CO--, R₅ S-- or ##STR58##

R₂ represents a hydrogen atom or a lower alkyl group;

R₃ represents a hydrogen atom, a phenyl group, a lower alkyl group, or asubstituted lower alkyl group in which the substituent is hydroxy,phenyl-lower alkoxy, amino, guanidino, N-nitroguanidino, carboxyl, loweralkoxycarbonyl, phenyl-lower alkoxycarbonyl, carbamoyl, mercapto, loweralkylthio, phenyl, hydroxyphenyl, indolyl or imidazolyl; or R₂ and R₃form a heterocyclic ring together with the nitrogen and carbon atoms towhich they are respectively bonded; R₄ represents a lower alkyl group, alower alkoxy group, a phenyl group, a substituted phenyl group, aphenyl-lower alkyl group, a substituted phenyl-lower alkyl group, aphenyl-lower alkoxy group, a substituted phenyl-lower alkoxy group, aphenoxy group, or a substituted phenoxy group; R₅ represents a loweralkyl group, a phenyl group, a substituted phenyl group, a phenyl-loweralkyl group, a substituted phenyl-lower alkyl group, ##STR59## or anamino(-carboxy)lower alkyl group; R₆ represents a hydrogen atom or alower alkyl group; R₇ represents a lower alkyl group, a phenyl group ora substituted phenyl group; X represents an oxygen or sulfur atom; andthe substituent in the substituted phenyl group is a halogen atom, alower alkyl group, or a lower alkoxy group; and salts of saidderivatives.

U.S. Pat. No. 4,316,906 to Ondetti et al discloses ether and thioethermercaptoacyl prolines of the formula ##STR60## wherein

the group X--R₁ is located at the 3- or 4-position in the ring;

X is oxygen or sulfur;

R is hydrogen or lower alkyl;

R₁ is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, 1- or2-adamantyl, aryl, substituted aryl, phenyl-lower alkylene orsubstituted phenyl-lower alkylene.

R₂ and R₃ are independently selected from hydrogen, lower alkyl, andtrifluoromethyl;

R₄ is hydrogen, R₅ --CO-- or ##STR61##

R₅ is lower alkyl, phenyl, phenyl-lower alkylene; substituted phenyl, orsubstituted phenyl-lower alkylene;

n is 0, 1 or 2; and salts thereof.

This Ondetti et al patent covers zofenopril

DESCRIPTION OF THE INVENTION

In accordance with the present invention, a method is provided forinhibiting onset of or treating migraine headaches wherein atherapeutically effective amount of an angiotensin converting enzymeinhibitor alone or in combination with a calcium channel blocker issystemically, such as orally or parenterally, administered over aprolonged period, whereby frequency and intensity of migraine headachesare significantly reduced.

Where a combination of ACE inhibitor and calcium channel blocker are tobe used, the ACE inhibitor will be employed in a weight ratio to thecalcium channel blocker of within the range of from about 0.1:1 to about10:1 and preferably from about 0.4:1 to about 2.5:1.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes substituted proline derivatives, such as any of those disclosedin U.S. Pat. No. 4,105,776 to Ondetti et al mentioned above, withcaptopril, that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,being preferred, carboxyalkyl dipeptide derivatives, such as any ofthose disclosed in European Patent Application No. 0 012 401 mentionedabove, with N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, thatis, enalapril, being preferred.

Other examples of angiotensin converting enzyme inhibitors suitable foruse herein include any of the phosphonate substituted amino or iminoacids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolinebeing preferred, phosphinylalkanoyl prolines disclosed in U.S. Pat. No.4,168,267 mentioned above with fosinopril being preferred, mercaptoacylderivatives of substituted prolines, disclosed in U.S. Pat. No.4,316,906 with zofenopril being preferred, any of the phosphinylalkanoylsubstituted prolines disclosed in U.S. Pat. No. 4,337,201 discussedabove, and the phosphonamidates disclosed in U.S. Pat. No. 4,432,971discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European patent Nos. 80822 and60668; Chugai's MC-838 disclosed in CA. 102:72588v and Jap. J.Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]-amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Pat. No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechst) disclosed in Eur. Pat. No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung35:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R_(o) 31-2201 (Hoffman-LaRoche) disclosed inFEBS Lett. 165:201 (1984); lisinopril (Merck) disclosed in Curr. Therap.Res. 37:342 (1985) and Eur. patent appl. No. 12-401, indalapril(delapril) disclosed in U.S. Pat. No. 4,385,051; rentiapril (fentiapril,Santen) disclosed in Clin. Exp. Pharmacol. Physiol. 10:131 (1983);indolapril (Schering) disclosed in J. Cardiovasc. Pharmacol. 5:643, 655(1983); spirapril (Schering) disclosed in Acta. Pharmacol. Toxicol. 59(Supp. 5):173 (1986); perindopril (Servier) disclosed in Eur. J. Clin.Pharmacol. 31:519 (1987); quinapril (Warner-Lambert) disclosed in U.S.Pat. No. 4,344,949 and CI 925 (Warner-Lambert) ([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino[-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

The calcium antagonist which will be used herein may be diltiazem whichis disclosed in U.S. Pat. No. 3,562,257 and which has the chemical name3-(acetyloxy)-5-[2-(dimethylamino)ethyl-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-oneand the structure ##STR63##

4-Phenyl-1,4-dihydropyridine calcium antagonists may be employed whichwill have the structure ##STR64## wherein R₁ and R₂ may be the same ordifferent and are lower alkyl or lower alkoxy (lower alkyl) where loweralkyl and lower alkoxy contain 1 to 4 carbons.

The above compounds and methods for preparing same are disclosed in U.S.Pat. Nos. 3,644,627, 3,485,847, 3,488,359, 3,574,843, 3,799,934,3,932,645 and 4,154,839 which are incorporated herein by reference.

The dihydropyridine calcium antagonist present in the composition of theinvention will preferably by nifedipine, that is, the compound offormula C wherein R₁ CH₃, R₂ is CH₃ and NO₂ is at the 2-position,namely, ##STR65## which is disclosed in U.S. Pat. Nos. 3,644,627 and3,485,847.

Other preferred 4-phenyl-1,4-dihydropyridine calcium antagonistssuitable for use herein include niludipine, that is, the compound offormula C wherein R₁ is --(CH₂)₂ OC₃ H₇, R₂ is --(CH₂)₂ OC₃ H₇ and NO₂is at the 3-position (disclosed in U.S. Pat. Nos. 3,488,359 and3,574,843); nimedipine, that is the compound of formula C wherein R₁ is--(CH₂)₂ OCH₃, R₂ is --CH(CH ₃)₂ and NO₂ is at the 3-position (disclosedin U.S. Pat. Nos. 3,799,934 and 3,932,645); nitrendipine, that is, thecompound of formula C wherein R₁ is --CH₂ CH₃, R₂ is --CH₃ and NO₂ is atthe 3-position (disclosed in U.S. Pat. Nos. 3,799,934 and 3,932,645);and nisoldipine, that is, the compound of formula C wherein R₁ is --CH₃,R₂ is -- CH₂ CH(CH₃)₂ and NO₂ is at the 2-position (disclosed in U.S.Pat. Nos. 3,799,934, 3,932,645 and 4,154,839). Verapamil may also beemployed.

The disclosure of the above-mentioned U.S. patents are incorporatedherein by reference.

In carrying out the method of the present invention, the angiotensinconverting enzyme inhibitor alone or in combination with the calciumchannel blocker may be administered to mammalian species, such asmonkeys, dogs, cats, rats and humans, and as such may be incorporated ina conventional systemic dosage form, such as a tablet, capsule, elixiror injectable. The above dosage forms will also include the necessarycarrier material, excipient, lubricant, buffer, antibacterial, bulkingagent (such as mannitol), anti-oxidants (ascorbic acid of sodiumbisulfite) or the like. Oral dosage forms are preferred, althoughparenteral forms such as intramuscular, intraperitoneal, or intravenousare quite satisfactory as well.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

Thus, for oral administration, a satisfactory result may be obtainedemploying the ACE inhibitor in an amount within the range of from about0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg toabout 25 mg/kg alone or in combination with the calcium channel blockerin an amount within the range of from about 0.01 mg/kg to about 100mg/kg and preferably from about 0.1 mg/kg to about 25 mg/kg with the ACEinhibitor and calcium channel blocker being employed together in thesame oral dosage form or in separate oral dosage forms taken at the sametime.

A preferred oral dosage form , such as tablets or capsules, will containthe ACE inhibitor in an amount of from about 0.1 to about 500 mg,preferably from about 125 to about 200 mg, and more preferably fromabout 25 to about 150 mg, alone or with the calcium channel blocker inan amount of from about 1 to about 350 mg, preferably from about 2 toabout 200 mg, and more preferably from about 30 to about 150 mg.

For parenteral administration, the ACE inhibitor will be employed in anamount within the range of from about 0.005 mg/kg to about 10 mg/kg andpreferably from about 0.01 mg/kg to about 1 mg/kg, alone or with thecalcium channel blocker in an amount within the range of from about0.005 mg/kg to about 20 mg/kg and preferably from about 0.01 mg/kg toabout 2 mg/kg.

The composition described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

Tablets of various sizes can be prepared, e.g., of about 50 to 700 mg intotal weight, containing one or both of the active substances in theranges described above, with the remainder being a physiologicallyacceptable carrier of other materials according to acceptedpharmaceutical practice. These tablets can, of course, be scored toprovide for fractional doses. Gelatin capsules can be similarlyformulated.

Liquid formulations can also be prepared by dissolving or suspending oneor the combination of active substances in a conventional liquid vehicleacceptable for pharmaceutical administration so as to provide thedesired dosage in one to four teaspoonsful.

Such dosage forms can be administered to the patient on a regimen of oneto four doses per day.

According to another modification, in order to more finely regulate thedosage schedule, the active substances may be administered separately inindividual dosage units at the same time or carefully coordinated times.Since blood levels are built up and maintained by a regulated scheduleof administration, the same result is achieved by the simultaneouspresence of the two substances. The respective substances can beindividually formulated in separate unit dosage forms in a mannersimilar to that described above.

Fixed combinations of ACE inhibitor and calcium channel blocker are moreconvenient and are preferred, especially in tablet or capsule form fororal administration.

In formulating the compositions, the active substances, in the amountsdescribed above, are compounded according to accepted pharmaceuticalpractice with a physiologically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc., in the particular typeof unit dosage form.

Illustrative of the adjuvants which may be incorporated in tablets arethe following: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate or cellulose; adisintegrating agent such as corn starch, potato starch, alginic acid orthe like; a lubricant such as stearic acid or magnesium stearate; asweetening agent such as sucrose, lactose or saccharin; a flavoringagent such as orange, peppermint, oil of wintergreen or cherry. When thedosage unit form is a capsule, it may contain in addition to materialsof the above type a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets or capsules may be coatedwith shellac, sugar or both. A syrup of elixir may contain the activecompound, water, alcohol or the like as the carrier, glycerol assolubilizer, sucrose as sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange.

Many of the active substances described above form commonly known,pharmaceutically acceptable salts such as alkali metal and other commonbasic salts or acid addition salts, etc. References to the basesubstances are therefore intended to include those common salts known tobe substantially equivalent to the parent compound.

The formulations as described above will be administered for a prolongedperiod, that is, for as long as the potential for onset of a migraineheadache remains or the symptoms of a migraine headache continue.Sustained release forms of such formulations which may provide suchamounts biweekly, weekly, monthly and the like may also be employed. Adosing period of at least two weeks and preferably at least 4 to 6 weeksare required to achieve minimal benefit.

The following Examples represent preferred embodiments of the presentinvention.

EXAMPLE 1

A captopril formulation suitable for oral administration in inhibitingonset of or treating a migraine headache is set out below.

1000 tablets each containing 25 mg of1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline were produced from thefollowing ingredients.

    ______________________________________                                        1-[(2S)--3-Mercapto-2-methylpropionyl]-                                                                  25    g                                            L-proline (captopril)                                                         Corn starch                50    g                                            Gelatin                    7.5   g                                            Avicel (microcrystalline cellulose)                                                                      25    g                                            Magnesium stearate         2.5   g                                            ______________________________________                                    

The captopril and corn starch are admixed with an aqueous solution ofthe gelatin. The mixture is dried and ground to a fine powder. TheAvicel and then the magnesium stearate are admixed with the granulation.This is then compressed in a tablet to form 1000 tablets each containing25 mg of active ingredient which is used for inhibiting onset of ortreating migraine headache.

EXAMPLE 2

By substituting 50 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline forthe captopril in Example 1, 1000 tablets each containing 50 mg of the1-(3-mercapto-2-D-methylpropanoyl)-L-proline are produced which isuseful in treating or inhibiting onset of migraine headache.

EXAMPLE 3

1000 tablets each containing 100 mg of captopril and 500 mgcarbamazepine are produced from the following ingredients:

    ______________________________________                                        Captopril              100    g                                               Lactose                100    g                                               Avicel                 150    g                                               Corn starch            50     g                                               Magnesium stearate     5      g                                               ______________________________________                                    

The captopril, lactose and Avicel are admixed, then blended with thecorn starch. Magnesium stearate is added. The dry mixture is compressedin a tablet press to form 1000 1205 mg tablets each containing 600 mg ofactive ingredients. The tablets are coated with a solution of Methocel E15 (methyl cellulose) including as a color a lake containing yellow #6.The resulting tablets are useful in treating or inhibiting onset ofmigraine headache.

EXAMPLE 4

Two piece #1 gelatin capsules each containing 25 mg of captopril and 100mg of carbamazepine are filled with a mixture of the followingingredients:

    ______________________________________                                        Captopril             25     mg                                               Magnesium stearate    7      mg                                               USP lactose           193    mg.                                              ______________________________________                                    

The resulting capsules are useful in treating or inhibiting onset ofmigraine headache.

EXAMPLE 5

An injectable solution for use in treating or inhibiting onset ofmigraine headache trigeminal neuralgia is produced as follows:

    ______________________________________                                        Captopril              500    mg                                              Methyl paraben         5      mg                                              Propyl paraben         1      mg                                              Sodium chloride        25     g                                               Water for injection qs.                                                                              5      l.                                              ______________________________________                                    

The captopril, preservatives and sodium chloride are dissolved in 3liters of water for injection and then the volume is brought up to 5liters. The solution is filtered through a sterile filter andaseptically filled into presterilized vials which are then closed withpresterilized rubber closures. Each vial contains 5 ml of solution in aconcentration of 100 mg of active ingredient per ml of solution forinjection for treating or inhibiting onset of migraine headache.

EXAMPLE 6

Tablets for use in treating or inhibiting onset of migraine headache areprepared as described in Example 1 except thatN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) isused in place of captopril.

EXAMPLE 7

An injectable for use in treating or inhibiting onset of migraineheadache is prepared as described in Example 5 except thatN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) isemployed in place of captopril.

EXAMPLE 8

A zofenopril formulation suitable for oral administration in treating orinhibiting onset of migraine headache is set out below.

1000 tablets each containing 100 mg of zofenopril are produced from thefollowing ingredients.

    ______________________________________                                        [1(S),4(S)]--1-[3-(benzoylthio)-2-                                                                     100    g                                             methyl-1-oxopropyl-4-(phenylthio)-                                            L-proline (zofenopril)                                                        Corn starch              50     g                                             Gelatin                  7.5    g                                             Avicel (microcrystalline cellulose)                                                                    25     g                                             Magnesium stearate       2.5    g                                             ______________________________________                                    

The zofenopril and corn starch are admixed with an aqueous solution ofthe gelatin. The mixture is dried and ground to a fine powder. TheAvicel and then the magnesium stearate are admixed with the granulation.This is then compressed in a tablet to form 1000 tablets each containing100 mg of active ingredient which is used for treating or inhibitingonset of migraine headache.

EXAMPLE 9

By substituting 100 g of fosinopril for the zofenopril in Example 8,1000 tablets each containing 100 mg of the fosinopril are produced whichis useful in treating or inhibiting onset of migraine headache.

EXAMPLE 10

1000 tablets each containing 200 mg of fosinopril and 200 mg ofcarbamazepine are produced from the following ingredients:

    ______________________________________                                        Fosinopril             100    g                                               Lactose                100    g                                               Avicel                 150    g                                               Corn starch            50     g                                               Magnesium stearate     5      g                                               ______________________________________                                    

The fosinopril, carbamazepine, lactose and Avicel are admixed, thenblended with the corn starch. Magnesium stearate is added. The drymixture is compressed in a tablet press to form 1000 705 mg tablets eachcontaining 300 mg of active ingredients. The tablets are coated with asolution of Methocel E 15 (methyl cellulose) including as a color a lakecontaining yellow #6. The resulting tablets are useful in treating orinhibiting onset of migraine headache.

EXAMPLE 11

Tablets for use in treating or inhibiting onset of migraine headache areprepared as described in Example 1 except that1-[N-[hydroxy-(4-phenylbutyl)phosphinyl]-L-alanyl-L-proline, disodiumsalt (prepared as described in U.S. Pat. No. 4,432,971) is used in placeof captopril.

EXAMPLE 12

An injectable for use in treating or inhibiting onset of migraineheadache is prepared as described in Example 5 except that1-[N-[hydroxy(4-phenylbutyl)phosphinyl]-L-alanyl]-L-proline, disodiumsalt (prepared as described in U.S. Pat. No. 4,432,971) is used in placeof captopril.

EXAMPLE 13

A captopril-diltiazem formulation suitable for oral administration inthe treatment of migraine headache is set out below.

1000 tablets each containing 100 mg of1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline and 100 mg of diltiazemare produced from the following ingredients:

    ______________________________________                                        1-(2S)--3-mercapto-2-methylpropionyl]-L-                                                                100    g                                            proline (captopril)                                                           Diltiazem                 100    g                                            Corn starch               50     g                                            Gelatin                   7.5    g                                            Avicel (microcrystalline cellulose)                                                                     25     g                                            Magnesium stearate        2.5    g                                            ______________________________________                                    

The captopril, diltiazem and corn starch are admixed with an aqueoussolution of the gelatin. The mixture is dried and ground to a finepowder. The Avicel and then the magnesium stearate are admixed with thegranulation. This is then compressed in a tablet to form 1000 tabletseach containing 200 mg of active ingredients which is used forpreventing or treating migraine headache.

EXAMPLE 14

By substituting 100 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-prolinefor the captopril in Example 13, 1000 tablets each containing 100 mg ofthe 1-(3-mercapto-2-D-methylpropanoyl)-L-proline and 100 mg diltiazemare produced which is useful in preventing or treating migraineheadache.

EXAMPLE 15

1000 tablets each containing 200 mg of captopril and 200 mg nifedipineare produced from the following ingredients:

    ______________________________________                                        Captopril              200    g                                               Nifedipine             200    g                                               Lactose                100    g                                               Avicel                 150    g                                               Corn starch            50     g                                               Magnesium stearate     5      g                                               ______________________________________                                    

The captopril, diltiazem, lactose and Avicel are admixed, then blendedwith the corn starch. Magnesium stearate is added. The dry mixture iscompressed in a tablet press to form 1000 505 mg tablets each containing200 mg of each active ingredient. The tablets are coated with a solutionof Methocel E 15 (methyl cellulose) including as a color a lakecontaining yellow #6. The resulting tablets are useful in preventing ortreating migraine headache.

EXAMPLE 16

Two piece #1 gelatin capsules each containing 250 mg of enalapril and150 mg of nitrendipine are filled with a mixture of the followingingredients:

    ______________________________________                                        Enalapril              250    mg                                              Nitrendipine           150    mg                                              Magnesium stearate     7      mg                                              USP lactose            193    mg                                              ______________________________________                                    

The resulting capsules are useful in preventing or treating migraineheadache.

EXAMPLE 17

An injectable solution for use in treating or preventing migraineheadache is produced as follows:

    ______________________________________                                        Captopril              500    mg                                              Diltiazem              300    mg                                              Methyl paraben         5      g                                               Propyl paraben         1      g                                               Sodium chloride        25     g                                               Water for injection qs.                                                                              5      L.                                              ______________________________________                                    

The captopril, diltiazem, preservatives and sodium chloride aredissolved in 3 liters of water for injection and then the volume isbrought up to 5 liters. The solution is filtered through a sterilefilter and aseptically filled into presterilized vials which are thenclosed with presterilized rubber closures. Each vial contains 5 ml ofsolution in a concentration of 100 mg of active ingredient per ml ofsolution for injection.

EXAMPLE 18

Tablets for use in preventing or treating migraine headache are preparedas described in Example 13 except thatN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) isused in place of captopril and nifedipine is used in place of diltiazem.

EXAMPLE 19

Tablets for use in treating or preventing migrane headache are preparedfollowing the procedure of Example 13 except that zofenopril is employedin place of captopril and nisoldipine is used in place of diltiazem.

EXAMPLE 20

Tablets for use in treating or preventing migraine headache are preparedfollowing the procedure of Example 13 except that fosinopril is employedin place of captopril.

EXAMPLE 21

Tablets for use in treating or preventing migraine headache are preparedfollowing the procedure of Example 13 except that alacepril is employedin place of captopril.

EXAMPLE 22

Tablets for use in treating or preventing migraine headache are preparedfollowing the procedure of Example 13 except that(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor lisinopril is employed in place of captopril.

What is claimed is:
 1. A method for inhibiting onset or treatingmigraine headache in a mammalian specie, which comprises administeringto a mammalian specie in need of such treatment an effective amount ofan angiotensin converting enzyme inhibitor alone or in combination witha calcium channel blocker over a prolonged period of treatment to reducefrequency and/or severity of migraine headaches during such period oftreatment.
 2. The method as defined in claim 1 wherein the angiotensinconverting enzyme inhibitior is a phosphonate substituted amino or iminoacid or salt thereof,, a substituted proline derivative, a carboxyalkyldipeptide derivative, a phosphinylalkanoyl proline derivative or aphosphonamidate derivative.
 3. The method as defined in claim 1 whereinsaid angiotensin converting enzyme inhibitor alone or in combinationwith a calcium channel blocker is administered orally or parenterally.4. The method as defined in claim 1 wherein said angiotensin convertingenzyme inhibitor alone or in combination with a calcium channel blockeris admixed with a pharmaceutically acceptable carrier therefor.
 5. Themethod as defined in claim 1 wherein said angiotensin converting enzymeinhibitor is a substituted proline derivative.
 6. The method as definedin claim 1 wherein said angiotensin converting enzyme inhibitor is acarboxyalkyl dipeptide derivative.
 7. The method as defined in claim 1wherein said angiotensin converting enzyme inhibitor is aphosphinylalkanoyl proline derivative, a phosphoramidate derivative, ora phosphonate substituted amino or imino acid or salt thereof.
 8. Themethod as defined in claim 1 wherein said angiotensin converting enzymeinhibitor is captopril which is optionally administered with a calciumchannel blocker in single or separate dosage forms.
 9. The method asdefined in claim 1 wherein said angiotensin converting enzyme inhibitoris enalapril.
 10. The method as defined in claim 1 wherein saidangiotensin converting enzyme inhibitor is1-[N-[hydroxy(4-phenylbutyl)-phosphinyl]-2-alanyl]-L-proline or itsdisodium salt.
 11. The method as defined in claim 1 wherein saidangiotensin converting enzyme inhibitor is administered in single ordivided doses of from about 0.1 to about 500 mg/one to four times dailyand where present the calcium channel blocker is administered in singleor divided doses of from about 1 to about 300 mg/1 to 4 times daily. 12.The method as defined in claim 1 wherein said angiotensin convertingenzyme inhibitor is captopril and is administered systemically in anamount of from about 0.1 to about 500 mg/1 to 4 times a day.
 13. Themethod as defined in claim 1 wherein the angiotensin converting enzymeinhibitor is administered with a calcium channel blocker.
 14. The methodas defined in claim 13 wherein the calcium channel blocker is diltiazemor a 4-phenyl-1,4-dihydropyridine.
 15. The method as defined in claim 14wherein the 4-phenyl-1,4-dihydropyridine is nifedipine.
 16. The methodas defined in claim 13 wherein the angiotensin converting enzymeinhibitor is employed in a weight ratio to the calcium channel blockerof within the range of from about 0.1:1 to about 10:1.